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We recently demonstrated that ex vivo activation of SMAD‐independent bone morphogenetic protein 4 (BMP4) signaling in hematopoietic stem/progenitor cells (HSPCs) influences their homing into the bone marrow (BM). Here, we assessed whether alterations in BMP signaling in vivo affects adult hematopoiesis by affecting the BM niche. We demonstrate that systemic inhibition of SMAD‐dependent BMP signaling by infusion of the BMP antagonist noggin (NGN) significantly increased CXCL12 levels in BM plasma leading to enhanced homing and engraftment of transplanted HSPCs. Conversely, the infusion of BMP7 but not BMP4, resulted in decreased HSPC homing. Using ST2 cells as an in vitro model of BM niche, we found that incubation with neutralizing anti‐BMP4 antibodies, NGN, or dorsomorphin (DM) as well as knockdown of  Smad1/5  and  Bmp4 , all enhanced CXCL12 production. Chromatin immunoprecipitation identified the SMAD‐binding element in the  CXCL12  promoter to which SMAD4 binds. When deleted, increased CXCL12 promoter activity was observed, and NGN or DM no longer affected  Cxcl12  expression. Interestingly, BMP7 infusion resulted in mobilization of only short‐term HSCs, likely because BMP7 affected CXCL12 expression only in osteoblasts but not in other niche components. Hence, we describe SMAD‐dependent BMP signaling as a novel regulator of CXCL12 production in the BM niche, influencing HSPC homing, engraftment, and mobilization. S tem  C ells   2014;32:3012–3022

SMAD Signaling Regulates CXCL12 Expression in the Bone Marrow Niche, Affecting Homing and Mobilization of Hematopoietic Progenitors